Intermediates and method of making camptothecin and camptothecin analogs

ABSTRACT

Compounds of Formula I ##STR1## are made in accordance with the following scheme: ##STR2## wherein R may be loweralkyl; R 1  may be H, loweralkyl, loweralkoxy, or halo; R 2 , R 3 , R 4 , and R 5  may each independently be H, amino, hydroxy, loweralkyl, loweralkoxy, loweralkylthio, di(loweralkyl)amino, cyano, methylenedioxy, formyl, nitro, halo, trifluoromethyl, aminomethyl, azido, amido, hydrazino, or any of the twenty standard amino acids bonded to the A ring via the amino-nitrogen atom; Y is H and W and X are halogen. Also disclosed are novel processes for making starting materials for the scheme given above, and novel intermediates employed in these processes.

FIELD OF THE INVENTION

The present invention provides a parallel synthesis of camptothecin andcamptothecin analogs via novel intermediates at high yields.

BACKGROUND OF THE INVENTION

Camptothecin (Chem. Abstracts Registry No. 7689-03-4) is a naturallyoccuring compound found in Camptotheca acuminata (Nyssaceae) which hasanti-leukemic and antitumor properties. Numerous camptothecin analogshaving like properties are known, examples being those described in U.S.Pat. No. 4,894,456 to Wall et al. and European Patent Application No. 0325 247 of Yaegashi et al.

A number of syntheses for camptothecin are known Several routes arereviewed in Natural Products Chemistry, Vol. 2, 358-361 (K. Nakanishi,T. Goto, S. Ito, S. Natori and S. Nozoe eds.) and in J. Cai and C.Hutchinson, Camptothecin, in The Alkaloids, Vol XXI, 101-137 (AcademicPress 1983). The biosynthesis of camptothecin is described in NaturalProducts Chemistry, Vol. 3, 573-574 (K. Nakanishi et al. eds.). A recentsynthetic route is described in U.S. Pat. No. 4,894,456 to Wall et al.(see also references cited therein).

A problem with prior methods of synthesizing camptothecin is that theyare largely linear syntheses. Such syntheses provide low yields of thefinal product because of the sequential loss in product during each stepof the total synthesis. Parallel syntheses (i.e., a strategy in whichtwo synthetic paths are followed separately and the products thereofcombined to form the final product) provide higher yields, but few suchsyntheses have been available for camptothecin. Accordingly, an objectof the present invention is to provide a parallel synthetic method formaking camptothecin and analogs thereof.

SUMMARY OF THE INVENTION

The present invention provides a method of making compounds of Formula Ibelow: ##STR3## wherein: R may be loweralkyl, preferably ethyl.

R₁ may be H, loweralkyl, loweralkoxy, or halo (e.g., chloro). PreferablyR₁ is H.

R₂, R₃, R₄, and R₅ may each independently be H, amino, hydroxy,loweralkyl, loweralkoxy, loweralkylthio, di(loweralkyl)amino, cyano,methylenedioxy, formyl, nitro, halo, trifluoromethyl, aminomethyl,azido, amido, hydrazino, or any of the twenty standard amino acidsbonded to the A ring via the amino-nitrogen atom (numbering in Formula Iis by the Le Men-Taylor numbering system and rings are lettered in theconventional manner. See J. Cai and C. Hutchinson, supra at 102).

At least two of R₂, R₃, R₄, and R₅ may be H, and in a preferredembodiment R₂, R₄, and R₅ are H.

Preferably: R₂ is H or amino; R₃ is H or hydroxy; R₄ is H; and R₅ is H.

In the invention, a compound of Formula I is produced according toscheme A below, where Y is H, R₁ through R₅ are as given in connectionwith Formula I above, X is halogen, preferably bromo or iodo; and W ishalogen, preferably chloro. ##STR4##

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "loweralkyl" means a linear or branched alkylgroup with 1-8, preferably 1-4, carbon atoms, such as methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, hexyl, and octyl. Thisdefinition also applies to a loweralkyl moiety in the loweralkoxy,loweralkylthio, and di(loweralkyl)amino groups. Thus, examples ofloweralkoxy groups are methoxy, ethoxy, propoxy, sec-butoxy, andisohexoxy; examples of loweralkylthio groups are methylthio, ethylthio,tert-butylthio, and hexylthio; and examples of di(loweralkyl)aminogroups are dimethylamino, diethylamino, diisopropylamino,di(n-butyl)amino, and dipentylamino.

The terms "halo" and "halogen" as used herein refers to a substituentwhich may be fluoro, chloro, bromo, or iodo.

Substituents on the "A" ring of the compounds disclosed herein may bejoined together to form a bifunctional substituent such as themethylenedioxy group. Methylenedioxy substituents may be bonded to anytwo consecutive positions in the A ring, for example, the 9,10, the10,11, or the 11,12 positions.

Substituents which are standard amino acids may be any of the twentyamino acids commonly found in naturally occuring proteins, and are wellknown in the art. These provide a substituent of the formula -NHCHRCOOH,with R being the side chain of any of the twenty standard amino acids.The amino acids may be of any configuration, but preferably have an (L)configuration.

A compound of Formula I is produced in accordance with Scheme A below byalkyating a pyridone of Formula III with a chloromethylquinoline ofFormula II to produce a compound of Formula IV, and then cyclizing thecompound of Formula IV to yield the compound of Formula I. ##STR5## InScheme A: Y is H; R and R₁ through R₅ are as given in connection withFormula I above; X is halogen, preferably bromo or iodo; and W ishalogen, preferably chloro.

The starting materials of Scheme A, the compounds of Formula II and III,are prepared in accordance with Schemes B and C below.

The pyridone of Formula III may be alkylated with a halomethylquinolineof Formula II in a suitable solvent, such as a polar protic solvent(e.g., isopropyl alcohol, ethanol, methanol), an aprotic solvent (e.g.,1,2-dimethoxyethan, tetrahydrofuran, toluene, acetonitrile, ordimethylformamide) or alternatively in an aqueous solution in thepresence of a phase transfer catalyst. The reaction is preferablycarried out under mildly basic conditions, to minimize attack on thepyridone ring oxygen. The reaction may be carried out in two stages by,first, forming the anion of of the pyridone by addition of an alkaliearth salt (e.g., potassium tert-butoxide) at about room temperature,and then adding the halomethylquinoline to the reaction solution andheating the solution between about 60° to about 100° Centigrade for 4-24hours.

The compound of Formula IV may be cyclized to yield the compound ofFormula I by an intramolecular Heck reaction. The reaction is carriedout in the presence of a palladium catalyst (e.g., palladium acatate)under basic conditions in a polar aprotic solvent such as acetonitrileor dimethylformamide. A phase transfer catalyst such as atetraalkylammonium halide salt is preferably included. The reactionshould be carried out in an inert atmosphere, such as under argon. Thereaction mixture may be heated to a temperature between about 50° toabout 100° C. for about 1 to 24 hours. Variations on these conditionswill be aparent from the literature on the Heck reaction. See, e.g., R.Grigg et al. Tetrahedron 46, 4003-4008 (1990).

The compounds of Formula II may be prepared in accordance with Scheme Bbelow, where R₁ through R₅ are as given in connection with Formula Iabove, and X is Bromo or Iodo, preferably Iodo. ##STR6##

The starting materials in Scheme B, the compounds of Formula V, are madeby known techniques, such as by chlorination of a quinoline. See, e.g.,Progress in Heterocyclic Chemistry 2, 180 (H. Suschitzky and E. Scriveneds. 1990). In the alternative, compounds of Formula V may be made fromthe substituted acetanilide as described by O. MethCohn et al., J. Chem.Soc. Perkin Trans. I 1981, 1520.

The halo group on the carboxaldehyde of Formula V is exchanged with anIodo or Bromo (preferably Iodo) to produce the carboxaldehyde of FormulaVI. The exchange reaction may be carried out in acetonitrile in thepresence of a catalytic amount of a strong acid, such as HCl, by heatingthe reaction mixture to between about 70° to about 90° C. for at leastabout 4 hours.

The carboxaldehyde of Formula VI is then reduced to produce thehydroxymethylquinoline of Formula VII. The reaction is carried out witha mild reducing agent to avoid reducing the quinoline ring, at atemperature of from about 0° to about 25° C., in an alcohol solvent. Analternative route for producing a compound of Formula VII is disclosedin N. Narasimham et al., J. Chem. Soc., Chem. Commun., 1985, 1368-1369.

A compound of Formula II is produced from the hydroxymethylquinoline ofFormula VII in accordance with conventional procedures in a solvent inwhich the reactants are soluble, such as dimethylformamide. The reactionis preferably carried out at lower temperatures to provide a higheryield.

The compounds of Formula III above are preferably prepared in accordancewith Scheme C below, wherein R is as given in connection with Formula Iabove, R₆ and R₇ are loweralkyl, preferably methyl, R₈ is loweralkyl,preferably ethyl, Y is Cl or H, and Z is halo, preferably bromo or iodo.##STR7##

The starting materials for Scheme C, the compounds of Formula VIII, maybe prepared in accordance with known techniques. For example, thesynthesis of 2-methoxy-3-pyridinecarboxaldehyde is disclosed in D.Comins and M. Killpack, J. Org. Chem. 55, 69-73 (1990).

In Scheme C, the carboxaldehyde of Formula VIII is halogenated toproduce the 4-halo-3-pyridinecarboxaldehyde of Formula IX. Halogenationat the 4- position may be carried out by reacting the carboxaldehyde ofFormula VIII with a lithiated diamine, such as lithiatedN,N,N'-trimethylethylenediamine, in dimethoxyethane or tetrahydrofuranto protect the aldehyde and direct subsequent C-4 lithiation, and bythen lithiating the C-4 position of the pyridine with a suitablelithiating reagent, such as n-butyllithium. See D. Comins and M.Killpack, supra. The C-4 lithiated pyridine intermediate is preferablyhalogenated by adding the intermediate to a solution of iodine orbromine in a polar or nonpolar organic solvent, preferably at atemperature of at least as low as about -70° C.

The compound of Formula IX is reduced in an alcoholic acidic media inthe presence of a trialkylsilane to yield the alkoxymethylpyridine ofFormula X. The acid should be a strong acid, such as sulfuric ortrifluoroacetic acid. At least about 2 molar equivalents of a suitablealcohol (e.g., methanol, ethanol, tert-butanol) should be included toconvert the aldehyde to the ether. Reference may be made to theliterature on the silane reduction of aldehydes for conditions andvariations on this reaction. See, e.g., M. Doyle et al., J. Am. Chem.Soc. 94 10, 3659-3661 (1972).

The compound of Formula X is lithiated at the C-4 position with alithiating agent such as n-butyllithium, and then reacted with acompound of Formula XI such as an alkyl α-ketobutyrate (e.g., methylα-ketobutyrate, ethyl α-ketobutyrate, tert-butyl α-ketobutyrate) toproduce the compound of Formula XII in essentially the manner describedby R. Lyle et al., J. Org. Chem. 38, 3268-3271 (1973). The reaction maybe carried out in a tetrahydrofuran or ether solvent at a temperature ofat least as low as about -50° C., with the alkyl α-ketobutyrate beingadded to the reaction solution as a single aliquot.

The compound of Formula XII is then cyclized to yield the compound ofFormula III. Cyclization may be carried out by reacting the compound ofFormula XII with bromo- or iodotrimethylsilane (preferablyiodotrimethylsilane) in a neutral or polar aprotic solvent such asacetonitrile, followed by reaction with a strong acid solution to cleavethe ethers and yield the compound of Formula III (the ring formingspontaneously upon cleavage of the ethers). The bromo- oriodotrimethylsilane is preferably generated in situ in accordance withknown techniques, such as by the reaction of chlorotrimethylsilane witha halogen salt or elemental halogen. See A. Schmidt, Aldrichimica Acta14, 31-38 (1981).

When Y is halo in the compound of Formula III, the compound may behydrogenated by any suitable technique, preferably by catalytichydrogenation in the presence of a palladium catalyst in a hydrogenatmosphere under pressure (e.g., at least three atmospheres). Seegenerally J. March, Advanced Organic Chemistry, 510-511 (3d. Ed. 1985).

As alternatives to Scheme C, a compound of Formula III, where Y is H,may be prepared in the manner described in D. Comins, Ph.D. Thesis,University of New Hampshire, Durham, N.H., at 25-29 (1977), and asdescribed in Lyle et al., J. Org. Chem. 38, 3268-3271 (1973).

The discussion herein is, for simplicity, given without reference tosterioisomerism. However, the compounds of Formula I have an asymmetriccarbon atom at the C-20 position. Thus, the present invention isconcerned with the synthesis of both (i) racemic mixtures of thecompound of Formula I and (ii) enantiomeric forms of the compound ofFormula I, particularly the 20-(S) form. The resolution of racematesinto enantiomeric forms can be done in connection with the last step ofthe process, or in preceeding steps involving the synthesis of anintermediate having an asymmetric carbon atom, by known procedures. Forexample, the racemate may be converted with an optically active reagentinto a diasteriomeric pair, and the diasteriomeric pair subsequentlyseparated into the enantiomeric forms.

Specific examples of compounds which may be prepared by the method ofthe present invention include 9-methoxy-camptothecin,9-hydroxy-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin,10-hydroxy-camptothecin, 10-nitro-camptothecin, 10-amino-camptothecin,10-chloro-camptothecin, 10-methyl-camptothecin, 11-methoxy-camptothecin,11-hydroxy-camptothecin, 11-nitro-camptothecin, 11-amino-camptothecin,11-formyl-camptothecin, 11-cyano-camptothecin, 12-methoxy-camptothecin,12-hydroxy-camptothecin, 12-nitro-camptothecin,10,11-dihydroxy-camptothecin, 10,11-dimethoxy-camptothecin,7-methyl-10-fluoro-camptothecin, 7-methyl-10-chloro-camptothecin,7-methyl-9,12-dimethoxy-camptothecin, 9,10,11-trimethoxy-camptothecin,10,11-methylenedioxy-camptothecin and9,10,11,12-tetramethyl-camptothecin.

Compounds of Formula I have antitumor and antileukemic activity.Additionally, compounds of Formula I wherein R₁ is halo are useful asintermediates for, among other things, making compounds of Formula Iwherein R₁ is loweralkyl.

Those skilled in the art will appreciate that additional changes can bemade in the compounds of Formula I (see, for examples, J. Cai and C.Hutchinson, supra), which changes will not adversely affect the newprocesses disclosed herein and do not depart from the concept of thepresent invention.

In the Examples which follow, "mg" means milligrams, "M" means Molar, mLmeans milliliter(s), "mmol" means millimole(s), "Bu" means butyl, "THF"means tetrahydrofuran, "h" means hours, "min" means minutes, "C" meansCentigrade, "p.s.i." means pounds per square inch, "DMF" meansdimethylformamide, "TLC" means thin layer chromatography, and "PLC"means preparative thin layer chromatography.

EXAMPLE 1 6-Chloro-2-methoxy-3-pyridinecarboxaldehyde

To a solution of tert-butyllithium (1.7M in pentane, 48.5 mL, 83.0 mmol)in 150 mL of THF at -78° C. was added 6-chloro-2-methoxypyridine (8.94mL, 75.0 mmol) over 5 min. The reaction mixture was stirred at -78° C.for 1 h, then dimethylformamide (7.55 mL, 97 mmol) was added and themixture was stirred at this temperature for 1.5 h. After the addition ofglacial acetic acid (8.6 mL, 150 mmol), the reaction mixture was allowedto warm to room temperature over a 30- min period, then diluted withether (200 mL). The organic phase was washed with saturated aqueousNaHCO₃ (100 mL) and brine (100 mL), and was dried over MgSO₄.Concentration afforded the crude product as a light yellow solid whichwas recrystallized from hexanes to give 9.6 g (75%) of6-chloro-2-methoxy-3-pyridinecarboxaldehyde as a white solid: mp 80°-81°C. (mp 62°-64° C.)(See Dainter, R. S.; Suschitzky, H.; Wakefield, B. J.Tetrahedron Lett. 1984, 25, 5693.). ¹ H NMR (300 MHz, CDCl₃) δ 10.31 (s,1H), 8.07 (d, 1H, J=9 Hz), 7.03 (d, 1H, J=9 Hz), 4.09 (s, 3H); IR(nujol) 1685, 1580, 1565, 1270, 1140, 1090, 1005, 905, 820, 755 cm⁻¹.

EXAMPLE 2 6-Chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde

To a solution of N,N,N'-trimethylethylenediamine (2.46 mL, 19.23 mmol)in 15 mL of 1,2-dimethoxyethane at mL 23° C. was added n-BuLi (9.22 mL,19.23 mmol), and the solution was stirred at -23° C. for 20 min. Themixture was transferred using a double-tipped needle to a solution of6-chloro-2-methoxy-3-pyridinecarboxaldehyde (3.0 g, 17.5 mmol) in 40 mLof 1,2-dimethoxyethane at -23° C. After stirring for 15 min, n-BuLi(12.6 mL, 26.2 mmol) was added and the dark mixture was stirred anadditional 2 h at -23° C. The solution was transferred using adouble-tipped needle to a solution of iodine (8.04 g, 31.7 mmol) in 40mL of 1,2-dimethoxyethane at -78° C. After stirring at -78° C. for 30min, the cooling bath was removed and the reaction mixture was allowedto warm for 20 min, then quenched with water. The mixture was extractedwith ether (2×30 mL) and the combined organic layers were washedsuccessively with 30-mL portions of 10% aqueous Na₂ S₂ O₃, water andbrine, and dried over MgSO4. Concentration afforded 4.62 g (89%) ofcrude product to which was added 50 mL of hexanes. The mixture wasstirred and allowed to stand at 5° C. overnight. Filtration gave 2.67 gof 6-Chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde as a yellow solid:mp 120°-124° C. Concentration of the hexane washings and purification ofthe residue by radial preparative thin-layer chromatography (silica gel,5% ethyl acetate/hexanes) gave an additional 1.41 g of product (mp120°-124° C.), raising the total yield of the compound to 78%.Recrystallization from hexanes gave analytical sample as a bright yellowsolid: mp 129°-130° C. ¹ H NMR (300 MHz, CDCl₃) δ 10.16 (s, 1H), 7.59(s, 1H), 4.07 (s, 1H); IR (nujol) 1690, 1350, 1260, 1095, 1010, 900, 840cm⁻¹.

EXAMPLE 3 2-Chloro-4-iodo-6-methoxy-5-(methoxymethyl)pyridine

To a mixture of 6-chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde (1.07g, 3.60 mmol), triethylsilane (0.86 mL, 5.40 mmol) and methanol (0.43mL, 10.6 mmol) at 0° C. was added trifluoroacetic acid (2.2 mL, 28.6mmol), and the resulting solution was stirred at 25° C. for 14 h Afterdilution with ether (30 mL), saturated NaHCO₃ was added until theaqueous phase was rendered basic. The aqueous layer was extracted withether (10 mL), and the combined ether layers were washed with water (10mL) and brine (10 mL), and dried (Na₂ SO₄). Concentration gave the crudeproduct which was purified by radial PLC (silica gel, 5% ethylacetate/hexanes) to afford2-chloro-4-iodo-6-methoxy-5-(methoxymethyl)pyridine as a white solid(1.05 g, 93%): mp 69°-72° C. Recrystallization from hexanes provided ananalytical sample: mp 74°-75° C. ¹ H NMR (300 MHz, CDCl₃) δ 7.40 (S,1H), 4.53 (s, 2H), 3.96 (s, 3H), 3.42 (s, 3H); IR (nujol) 1550, 1300,1115, 1090, 1020, 940, 905, 830, 720 cm⁻¹.

EXAMPLE 4 Ethyl 2-Hydroxy-2-(6'-chloro-2'-methoxy-3'-methoxymethyl-4'-pyridyl)butyrate

To a solution of 2-chloro-4-iodo-6-methoxy-5(methoxymethyl)pyridine(2.28 g, 7.30 mmol) in 50 mL of THF at -90° C. was added n-BuLi (3.46mL, 8.03 mmol) over 5 min and the resulting solution was stirred at -90°C. for 30 min. Ethyl o-ketobutyrate (1.25 mL, 9.45 mmol) was added, thereaction mixture was stirred at -90° C. for 30 min, then allowed to warmat ambient for 20 min, and quenched with saturated NH₄ Cl. After removalof most of the solvent under reduced pressure, the residue was taken upin 40 mL of ether, washed with dilute NaHCO₃ (15 mL) and brine (15 mL),and was dried over MgSO₄. Evaporation of the solvent in vacuo andpurification of the residue by radial PLC (10% acetone/hexanes) affordedethyl2-hydroxy-2-(6'-chloro-2'-methoxy-3'-methoxymethyl-4'-pyridyl)butyrate(1.53 g, 66%) as a light yellow, viscous oil. ¹ H NMR (300 MHz, CDCl₃) δ7.07 (s, 1H), 4.75 (d, 1H, J=12 Hz), 4.47 (d, 1H, J=12 Hz), 4.24 (q, 1H,J=6 Hz), 4.17 (q, 1H, J=6 Hz), 3.96 (s, 3H), 3.37 (s, 3H), 2.16 (m, 2H),1.24 (t, 3H, J=6 Hz); IR (film) 3400, 1735, 1580, 1555, 1305, 1235,1130, 1090, 1020, 905, 830, 730 cm⁻¹.

EXAMPLE 59-Chloro-7-oxopyrido[5,4-c1-2-oxo-3-ethyl-3-hydroxy-3,6-dihydropyran

To a stirred mixture of the hydroxy ester prepared in Example 4 above(1.53 g, 4.82 mmol) and sodium iodide (2.89 g, 19.3 mmol) in dry CH₃ CN(35 mL) at 25° C. was added dropwise chlorotrimethylsilane (2.45 mL,19.3 mmol). The resulting solution was heated at reflux for 4 h, thesolvent was removed under reduced pressure, and 100 mL of 6N HCl wasadded to the residue. After heating at a gentle reflux for 4 h, themixture was stirred at 25° C. overnight, then extracted with six 30-mLportions of CHCl₃ containing 5% CH₃ OH. The combined organic extractswere washed with 40 mL of half-saturated NaCl containing Na₂ S₂ O₃,followed by 40 mL of saturated NaCl. After drying over Na₂ SO₄, thesolvent was removed under reduced pressure and the residue was purifiedby radial PLC (silica gel, 5% CH₃ OH/CHCl₃ ) to give9-chloro-7-oxopyrido[5,4-c]-2-oxo-3-ethyl-3-hydroxy-3,6-dihydropyran(743 mg, 63%) as an off-white solid: mp 205°-207° C. Recrystallizationfrom CHCl₃ /CH₃ OH gave an analytically pure sample as a white solid: mp207°-208° C. ¹ H NMR (300 MHz, CDCl₃ DMSO-d6) δ 6.79 (s, 1H), 5.49 (d,1H, J=15 Hz), 5.13 (d, 1H, J=15 Hz), 1.78 (q, 2H, J=6 Hz), 0.93 (t, 3H,J=9 Hz), IR (nujol) 3450, 1740, 1640, 1600, 1560, 1320, 1225, 1140,1035, 995, 940 cm⁻¹.

EXAMPLE 6 7-Oxopyrido[5,4-c1-2-oxo-3-ethyl-3-hydroxy-3,6-dihydropyran

A mixture of the chloropyridone prepared in Example 5 above (400 mg,1.64 mmol) and sodium acetate (400 mg, 4.86 mmol) in 25 mL of ethanolwas hydrogenated over 10% Pd/C (100 mg) at 42 psi for 4 h. The mixturewas filtered through celite and the solids were washed with CH₃ OH. Thefiltrate was concentrated and the residue was purified by radial PLC(silica gel, 5% CH₃ OH/CHCl₃) to give the pure product (256 mg, 75%) asa white solid: mp 230°-232° C. (dec.). Recrystallization from CHCl₃ /CH₃OH afforded an analytical sample: mp 232° C. (dec.). 1H NMR (300 MHz,CHCl₃ /DMSO-d6) δ 7.30 (d, 1H, J=6 Hz), 6.49 (d, 1H, J=6 Hz), 5.42 (d,1H, J=18 Hz), 5.12 (d, 1H, J=18 Hz), 1.79 (m, 2H), 0.91 (t, 3H, J=6 Hz);IR (nujol) 3300, 1750, 1640, 1620, 1555, 1065, 1030, 995, 805, cm⁻¹.

EXAMPLE 7 2-Chloro-3-quinolinecarboxaldehyde

To a solution of 0.46 mL (3.30 mmol) of diisopropylamine in 8 mL of THFat 0° C. Was added 1.53 mL (3.30 mmol) of n-BuLi dropwise. After 20 minthe solution was cooled to -78° C. and 2-chloroquinoline (491 mg, 3.0mmol) was added neat. The mixture was stirred at -78° C. for 30 min,then dimethylformamide (0.39 mL, 5.04 mmol) was added dropwise and thereaction mixture was stirred an additional 30 min at this temperature.After quenching at -78° C. with glacial acetic acid (1 mL), the mixturewas warmed to room temperature and diluted with ether (30 mL). Theorganic phase was washed with saturated NaHCO₃ solution (10 mL) andbrine (10 mL), and was dried over MgSO₄. Concentration afforded2-chloro-3-quinolinecarboxaldehyde (530 mg, 92%) as a light yellow solid(mp 145°-149 ° C.), which was used directly in the next step withoutfurther purification. Recrystallization from ethyl acetate afforded thepure compound as light yellow needles: mp 149°-150° C. (mp 148°-149° C.reported in Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. PerkinTrans. I 1981, 1520.). 1H NMR (300 MHz, CDCl₃) δ 10.57 (s, 1H), 8.77 (s,1H), 8.08 (d, 1H, J=9 Hz), 8.0 (d, 1H, J=9 Hz), 7.90 (t, 1H, J=9 Hz),7.67 (t, 1H, J=9 Hz); IR (nujol) 1685, 1575, 1045, 760, 745 cm⁻¹.

EXAMPLE 8 Preparation of 2-Chloro-3-quinoline-carboxaldehyde fromacetanilide

Following a literature procedure (see Meth-Cohn, O.; Narhe, B.;Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520), phosphorusoxychloride (24.0 mL, 260 mmol) was added dropwise to an ice-coldsolution of dimethylformamide (7.20 mL, 93.0 mmol) and the deep-redsolution was stirred at 0° C. for 30 min. Acetanilide (5.0 g, 37.0 mmol)was added neat and the mixture was stirred at 0° C. for 30 min, thenheated at 75° C. for 16 h. The cooled mixture was poured into 250 mL ofice-water and stirred at 0°-5° C. for 30 min. The product was filtered,washed with water, and recrystallized from ethyl acetate to give 5.2 g(74%) of 2-Chloro-3-quinoline-carboxaldehyde as a light yellow solid: mp147°-149° C.

EXAMPLE 9 2-Iodo-3-quinolinecarboxaldehyde

A mixture of the aldehyde prepared in accordance with Example 7 or 8above (5.0 g, 26.2 mmol), sodium iodide (10.0 g, 66.7 mmol) andconcentrated HCl (1 mL) in 100 mL of CH₃ CN was heated at reflux for 4.5h. After removal of most of the solvent in vacuo, aqueous Na₂ CO₃ wasadded until the mixture was basic, and the product was filtered andwashed with water. The crude product was recrystallized from 95% ethanolto give 6.51 g (88%) of 2-iodo-3-quinolinecarboxaldehyde as off-whitefluffy needles: mp 156°-157° C. (mp 150°-152° C. reported in Meth-Cohn,O.; Narhe, B.; Tranowski, B.; Hayes, R.; Keyzad, A.; Rhavati, S.;Robinson, A. J. Chem. Soc. Perkin Trans. I 1981, 2509). ¹ H NMR (300MHz,CDCl₃) δ 10.29 (s, 1H), 8.57 (s, 1H), 8.12 (d, 1H, J=9 Hz), 7.98 (d,1H, J=9 Hz) 7.88 (t, 1H, J=9 Hz), 7.68 (t, 1H, J=9 Hz); IR (nujol) 1680,1610, 1570, 1555, 1315, 1020, 1005, 750, 740 cm⁻¹.

EXAMPLE 10 3-Hydroxymethyl-2-iodoquinoline

To a stirred solution of 2-iodo-3-quinolinecarboxaldehyde (595 mg, 2.10mmol) in 40 mL of CH₃ OH at 0° C. was added NaBH₄ (86 mg, 2.31 mmol),and the mixture was stirred at 0° C. for 30 min. After concentrating themixture to approximately one-half of its original volume, water (30 mL)was added and the mixture was allowed to stand at 5° C. overnight. Thesolids were filtered and the crude product (570 mg, was recrystallizedfrom methanol to give 3-hydroxymethyl-2-iodoquinoline (505 mg, 84%) ascolorless needles: mp 189°-190° C. ¹ H NMR (300 MHz, CDCl₃) δ 8.19 (s,1H), 7.99 (d, 1H, J=9 Hz), 7.87 (d, 1H, J=9 Hz), 7.68 (m, 1H), 7.58 (t,1H, J=9 Hz), 5.45 (t, 1H, J=6 Hz), 4.66 (d, 2H, J=6 Hz); IR (nujol)3350, 1580, 1320, 1125, 1060, 995, 755, 720, cm⁻¹.

EXAMPLE 11 3-Chloromethyl-2-iodoquinoline

To a stirred mixture of 3-hydroxymethyl-2iodoquinoline prepared inaccordance with Example 10 above (350 mg, 1.23 mmol) andtriphenylphosphine (483 mg, 1.84 mmol) in 10 mL of dry DMF at -23° C.was added N-chlorosuccinimide (246 mg, 1.84 mmol), and the mixture wasstirred for 1 h at -23° C. After the addition of 40 mL of dilute aqueousNaHCO₃, the mixture was extracted with ethyl acetate (20 mL) and thenether (2×15 mL). The combined organic extracts were washed successivelywith 20-mL portions of dilute NaHCO₃, water and brine, and were driedover MgSO₄. Concentration and purification of the residue by radial PLC(silica gel, 10% ethyl acetate/hexanes) afforded 312 mg (84%) of3-chloromethyl-2-iodoquinoline as a white crystalline solid: mp138°-140° C. Recrystallization from hexanes afforded an analyticalsample as colorless needles: mp 139°-140° C. ¹ H NMR (300 MHz, CDCl₃) δ8.17 (s, 1H), 8.07 (d, 1H, J=9 Hz), 7.84 (d, 1H, J=9 Hz), 7.75 (t, 1H,J=9 Hz), 7.62 (t, 1H, J=9 Hz), 4.80 (s, 1H); IR (nujol) 1585, 1555,1260, 1010, 780, 755, 710 cm⁻¹.

EXAMPLE 128-(2'-Iodo-3'-quinolylmethyl)-7-oxopyrido[5,4-c1-2-oxo-3-ethyl-3-hydroxy-3,6-dihydropyran

To a solution containing 45 mg (0.40 mmol) of potassium tert-butoxide in4 mL of dry isopropyl alcohol at 25° C. was added 55 mg (0.26 mmol) of7oxopyrido[5,4-c]-2-oxo-3-ethyl-3-hydroxy-3,6dihydropyran prepared inaccordance with Example 6 above and the mixture was stirred at 25° C.for 30 min. A solution of 3-chloromethyl-2-iodoquinoline prepared inaccordance with Example 11 above (104 mg, 0.35 mmol) in 1 mL of CH₃ OHwas added dropwise to the white suspension, and the resulting solutionwas heated at 75° C. for 24 h. After quenching the reaction mixture withsaturated NH₄ Cl, the solvents were removed under reduced pressure, andthe residue was taken up in CH₂ Cl₂ (20 mL) and washed with brine (2×10mL). Concentration and purification of the residue by radial PLC (2% CH₃OH/CHCl₃) gave the product (99 mg, 80%) as a white solid: mp 171°-174°C. (dec.). Recrystallization from ethyl acetate/hexanes afforded ananalytical sample: mp 174° C. (dec.). ¹ H NMR (300 MHz, CDCl₃) δ 8.05(d, 1H, J=9 Hz), 7.70-7.80 (m, 3H), 7.55-7.61 (m, 2H), 6.61 (d, 1H, J=9Hz), 5.63 (d, 1H, J=15 Hz), 5.43 (d, 1H, J=15 Hz), 5.27 (d, 1H, J=9 Hz),5.22 (d, 1H, J=9 Hz); IR (nujol) 3350, 1750, 1650, 1590, 1565, 1160,1140, 1000, 750 cm⁻¹.

EXAMPLE 13 (±)-Camptothecin

A mixture of8-(2'-iodo-3'-quinolylmethyl)-7-oxopyrido[5,4-c]-2-oxo-3-ethyl-3-hydroxy-3,6-dihydropyranprepared in accordance with Example 12 above (76 mg, 0.16 mmol), K₂ CO₃(44 mg, 0.32 mmol), tetrabutylammonium bromide (52 mg, 0.16 mmol) andPd(OAc)₂ (3.6 mg, 0.016 mmol) in 15 mL of dry acetonitrile under argonwas heated at 90° C. for 5 h. TLC analysis of the reaction mixtureshowed a single spot which was highly U.V. active. The mixture wascooled, concentrated, and the residue was taken up in 30 mL of CHCl₃containing 10% CH₃ OH. This was washed with two 10-mL portions ofsaturated aqueous NH₄ Cl. The organic layer was dried over Na₂ SO₄ andconcentrated. The dark residue was subjected to radial PLC (silica gel,4% CH₃ OH/CHCl₃), to give 17 mg of an orange solid which was shown byNMR analysis to be a mixture of impure (±)-camptothecin andtetrabutylammonium bromide. The aqueous washings were filtered to give ayellow solid which was purified by radial PLC (silica gel, 4% CH₃OH/CHCl₃) to afford (±)-camptothecin (26 mg, 47%) as a yellow solid: mp275°-277° C. (mp 275°-277° C. reported in Volman, R.; Danishefsky, S.;Eggler, J.; Soloman, D. M. J. Am. Chem. Soc. 1971, 93, 4074.).

The foregoing examples are illustrative of the present invention, andare not to be construed as limiting thereof. The invention is defined bythe following claims, with equivalents of the claims to be includedtherein.

That which is claimed is:
 1. A method of making a compound of Formula I:##STR8## wherein: R is loweralkyl;R₁ is H, loweralkyl, loweralkoxy, orhalo; and R₂ R₃, R₄, and R₅ are each independently H, amino, hydroxy,loweralkyl, loweralkoxy, loweralkylthio, di(loweralkyl)amino, cyano,methylenedioxy, formyl, nitro, halo, trifluoromethyl, aminomethyl,azido, amido, hydrazino, or any of the twenty standard amino acidsbonded to the A ring via the amino-nitrogen atom, and wheremethylenedioxy comprises R₂ and R₃, R₃ and R₄, or R₄ and R₅ takentogether; said method comprising cyclizing a compound of Formula IV##STR9## where X is halogen and Y is hydrogen, by an intramolecular Heckreaction in a polar aprotic solvent under basic conditions in thepresence of a palladium catalyst to yield a compound of Formula I.
 2. Amethod according to claim 1, wherein said palladium catalyst ispalladium acetate.
 3. A method according to claim 2, wherein said polaraprotic solvent is selected from the group consisting of acetonitrileand dimethylformamide.
 4. A method according to claim 2, wherein saidHeck reaction is carried out in an inert atmosphere.
 5. A methodaccording to claim 2, said solvent further containing a phase transfercatalyst.
 6. A compound of Formula IV: ##STR10## wherein: X is halogen;Yis hydrogen; R is loweralkyl; R₁ is H, loweralkyl, loweralkoxy, or halo;and R₂, R₃, R₄, and R₅ are each independently H, amino, hydroxy,loweralkyl, loweralkoxy, loweralkylthio, di(loweralkyl)amino, cyano,methylenedioxy, azido, amido, hydrazino, or any of the twenty standardamino acids bonded to the A ring via the amino-nitrogen atom, and wheremethylenedioxy comprises R₂ and R₃, R₃ and R₄ or R₄ and R₅ takentogether.
 7. A compound according to claim 6, wherein X is selected fromthe group consisting of bromo and iodo.
 8. A compound according to claim6, wherein R is ethyl.
 9. A compound according to claim 6, wherein R₁ isH.
 10. A compound according to claim 6, wherein at least two of R₂, R₃,R₄, and R₅ are H.
 11. A compound according to claim 6, wherein R₂, R₄,and R₅ are H.
 12. A compound according to claim 6, wherein R₂ isselected from the group consisting of H and amino, R₃ is selected fromthe group consisting of H and hydroxy, R₄ is H, and R₅ is H.
 13. Acompound according to claim 6, wherein X is selected from the groupconsisting of bromo and iodo, R is ethyl, R₁ is H, R₂ is selected fromthe group consisting of H and amino, R₃ is selected from the groupconsisting of H and hydroxy, R₄ is H, and R₅ is H.
 14. A compoundaccording to claim 6, wherein X is iodo, R is ethyl, R₁ is H, R₂ is H,R₃ is H, R₄ is H, and R₅ is H.
 15. A compound of Formula IV: ##STR11##wherein: X is selected from the group consisting of bromo and iodo;Y ishydrogen; R is ethyl; R₁ is H, loweralkyl, loweralkoxy, or halo; and R₂R₃, R₄, and R₅ are each independently H, amino, hydroxy, loweralkyl,loweralkoxy, loweralkylthio, di(loweralkyl)amino, cyano, methylenedioxy,formyl, nitro, halo, trifluoromethyl, aminomethyl, azido, amido,hydrazino, or any of the twenty standard amino acids bonded to the Aring via the amino-nitrogen atom, and where methylenedioxy comprises R₂and R₃, R₃ and R₄, or R₄ and R₅ taken together.
 16. A compound accordingto claim 15, wherein R₁ is H.
 17. A compound according to claim 15,wherein at least two of R₂, R₃, R₄, and R₅ are H.
 18. A compoundaccording to claim 15, wherein R₂, R₄, and R₅ are H.
 19. A compoundaccording to claim 15, wherein R₂ is selected from the group consistingof H and amino, R₃ is selected from the group consisting of H andhydroxy, R₄ is H, and R₅ is H.
 20. A compound according to claim 15,wherein X is selected from the group consisting of bromo and iodo, R isethyl, R₁ is H, R₂ is selected from the group consisting of H and amino,R₃ is selected from the group consisting of H and hydroxy, R₄ is H, andR₅ is H.
 21. A compound according to claim 15, wherein X is iodo, R isethyl, R₁ is H, R₂ is H, R₃ is H, R₄ is H, and R₅ is H.